Severe loss of vision occurs due to age-related macular degeneration (AMD) and approximately 15 million people in the US have some form of AMD, which is expected to double by 2050. Most of the current clinical treatments are primarily focused on slowing down the progression of the disease, as there is neither a cure that can stop the degeneration nor a therapy, other than retinal prostheses, that can restore vision lost due to the degeneration. Current systems, however, are limited by poor resolution (higher electrode density requiring more current, leading to heat production), retinal damage over a time period and cellular overgrowth due to surgical implantation. Optogenetic sensitization of retinal cells has potential as an interim solution until the regenerative medicine is successful. In addition to higher resolution, optogenetics has advantages over electrical stimulation such as cellular specificity and does not require intraocular surgery. However, clinical translation of optogenetic enabled vision restoration suffers from the drawback of requiring an active stimulation by light source having intensity an order of magnitude higher than ambient light. To mitigate these problems, Nanoscope Technologies and its collaborators have developed a novel viral vector carried multi- characteristic opsin (vMCO) to sensitize retinal cells in degenerated dry-AMD retina. Our electrophysiology studies demonstrate that MCO sensitized retina is activatable by ambient light illumination. Further, we found that MCO expression in ON bipolar cells lasts at least 16 wks in rd10 mice, leading to significant improvement of visually guided behavior at ambient light level. The safety of vMCO in mice is confirmed by: no detectable phototoxicity after chronic light exposure, no detectable ocular damage, minimal quantities of vector in non- targeted organs, no increase of pro and anti-inflammatory cytokines in plasma, and no immune cells in retina after vMCO injection. Based on this success and feedback from FDA, we aim to further develop the product (vMCO) for restoring vision in subjects with retinal dystrophies in ambient light environment. The objectives of this project will be accomplished by: Aim 1: Quantify long-term stability of vMCO and safety of vMCO in dry- AMD mice model; Aim 2: Evaluate vMCO-enabled long-term vision restoration in ambient light environment using behavioral assays and electrophysiology in two different mice models (rd1 and rd10) and rcd1 dog model; and Aim 3: GLP Study of toxicity and biodistribution of intravitreally-injected vMCO in wild-type dogs. This collaborative effort brings together complementary expertise to address a challenging problem in retinal degenerative diseases. Upon completion of the Phase II SBIR we envision to advance: (i) further vMCO product development, (ii) efficacy/safety studies in non-human primate through Phase IIb, (iii) IND application submission to FDA, and (iv) partnering with venture capital and pharmaceutical company for commercialization. Success of this proposal will lead to a new clinical approach for treating patients with dry- AMD at ambient light environment.